Demiroglu Science University Florence Nightingale Journal of Transplantation2020;5(1-2):61-69 doi: 10.5606/dsufnjt.2020.017
The role of intestinal flora in autism and nutritional approaches
Aslı Melike Ekmekçi1, Oytun Erbaş1,2
1Institute of Experimental Medicine, Gebze-Kocaeli, Turkey 2Department of Physiology, Medical Faculty of Demiroğlu Bilim University, Istanbul, Turkey
ABSTRACT Autism spectrum disorder (ASD) is a social behavior disorder and awareness on ASD has been increasing nowadays. Social deficiencies and repetitive movements constitute the symptoms of ASD occurring in childhood. As there is no biological marker in autism, parental and clinician approaches are based on diagnosis. Genetic and environmental factors play a role in autism, and its prevalence has been increasing in recent years. The process and amount of exposure to environmental factors create differences in the cause of autism. Although it is unclear yet whether autism is a cause or result, impaired intestinal flora is among the symptoms of autism. Factors such as nutrition approaches and perinatal factors have been thought to play a role in intestinal flora dysbiosis. Metabolites that cross the blood-brain barrier in the intestinal flora dysbiosis can cause morphological changes in the hippocampus in the brain. Various dietary approaches and fecal microbiota transplantation have become candidates for autism treatment methods to improve the deteriorated flora. In this review, we discuss the effects of therapeutic nutritional approaches and fecal transplantation by examining the relationship between ASD and intestinal flora. Keywords: Autism spectrum disorder, intestinal flora, nutrition
Autism spectrum disorder (ASD) is a behavioral are heavy metals, antibiotics and chemical disorder characterized by language and social toxic substances. Other causes include diet, deficiencies that occur in childhood. Repetitive infections (Morbilli/measles, human herpesvirus behaviors, obsessions, and communication 6/HHV6, cytomegalovirus/CMV, Streptococci, difficulties are observed in autism. Autism was Clostridia, Borrelia, and Candida spp.), mode first described in the literature by the American of delivery, oxygen deficiency during delivery psychiatrist Leo Kanner as “early childhood and after delivery, and differences in cerebral schizophrenia” in 1943.[1] According to the blood supply. Autism is seen in children who National Health Statistics Report published in the cannot cope with environmental problems United States, the prevalence of autism, which due to their genetic tendencies, as a result was 1:86 in 2007, increased to 1:50 in 2012.[2] of a series of mechanisms. Therefore, these Factors such as increased awareness of physicians environmental factors in autism, the intestinal and parents, differences in diagnostic criteria, flora (microbiota) is differentiated. Differentiated widespread use of screening scales and keeping microbiota lead to gastrointestinal symptoms in accurate data are effective.[3] individuals with autism. Genetic and environmental factors play a role In this review, we discuss the effects of in the pathogenesis of ASD. Although single- microbiota, the effects of microbiota on autism, gene polymorphisms are effective in autism, nutritional approaches, and the effects of fecal autism does not occur without environmental microbiota transplantation (FMT) on autism as an factors. Among the major causes of autism alternative treatment method.[1,4]
Correspondence: Aslı Melike Ekmekçi. Deneysel Tıp Enstitüsü, 41470 Gebze-Kocaeli, Türkiye. e-mail: [email protected]
Cite this article as: Ekmekçi AM, Erbaş O. The role of intestinal flora in autism and nutritional approaches. D J Tx Sci 2020;5(1-2):61-69. 62 D J Tx Sci
INTESTINAL FLORA (MICROBIOTA) addition, almost all children with autism do not have a normal intestinal flora.[1,11,12] In a meta- The intestinal microbiota contains about analysis of 144 studies, constipation was found 3 million genes, or 150 times more genes to be in 4.3 to 45.5%, diarrhea in 2.3 to 75.6%, [5] than the human genome. Colonization in the and more than one symptom in 4.2 to 96.8%.[13] human body first begins with exposure to the mother's vaginal microbiota during delivery. The Abnormal intestinal functions in autism affect intestinal microbiota of infants delivered vaginally the brain due to increased permeability. The gut- is similar to the vaginal microbiota of their brain axis, which is a communication pathway mothers dominated by Lactobacillus, Prevotella or between the gut and the brain, has been accepted Sneathia spp., the intestinal microbiota of infants as a two-way communication system. The gut- delivered by cesarean section is Staphylococcus, brain axis plays a role in the pathogenesis of Corynebacterium and Propionibacterium spp., ASD. Intestinal microbiota affects brain function and observed to be similar to the skin microbiota through the neuro-endocrine, neuro-immune, of mothers.[6] autonomic nervous systems, and toxin production of the microbiota.[14] Stool samples that obtained There are two dominant types of bacteria from children with ASD revealed higher levels of in the human microbiota: Bacteroidetes and Clostridium histolyticum compared to samples Firmicutes filum. Proteobacteria, Actinobacteria, from healthy unrelated children. In addition, Fusobacteria and Verrucomicrobia phylum are intestinal dysbiosis has occurred in children less common.[7] The microbiome in the first with autism.[15] The main factor underlying the meconium of mice is not sterile, indicating that relationship between ASD and the intestine is the microbiome colonizes the infant intestines the increased permeability of the intestinal tract before birth.[8] Subsequent interactions with of individuals with ASD, and this is referred nutrition and the environment result in increased to as leaky gut[16] According to the leaky gut intestinal flora diversity. Microbial diversity differs hypothesis, the permeability of the mucosal among individuals in terms of diet, hygiene, barrier increased with reduced tight-junction social behavior, vaccination and genetic factors.[6] activity. Since the function of intestinal cells is Studies have revealed significantly more clostridia impaired, vitamins, minerals and other nutrients and ruminococcus in the stool of the autistic related to carrier proteins cannot pass into the group with gastrointestinal (GI) symptoms.[9] blood sufficiently. Therefore, related symptoms Hippocampal neurodevelopment was altered in of inadequacy occur. It has been suggested that two groups of mice whose microbiota was altered gliadamorphine and casomorphine, which are with germ-free antibiotics and consequently spatial partial digestive products of harmful substances and object recognition was impaired.[10] produced by microorganisms such as gliadin and casein, cross the intestinal barrier and affect the AUTISM - MICROBIOTA functions of the central nervous system (CNS) by passing to the blood and then to the brain. These A potential connection between microbiota opioid proteins cause behavioral changes in the and ASD has been suggested over two decades brain and gut, constipation, bloating and diarrhea. ago. Recent studies suggest that autism is a Morphine poisoning might be the most likely disease scene that begins in the gastrointestinal reason why children with autism are resistant system and shows results in the brain. First, oral to pain.[17,18] Although it is not clear whether the vancomycin therapy provides a short-term benefit impaired microbiota is the cause or the result of in a small group of children with ASD, and later, autism yet, metabolites have crossed the blood- intestinal bacteria research in children with ASD brain barrier and formed the gut brain axis as a revealed differences compared to the control result of the increased permeable flora. group. Since then, numerous studies from various cohorts have reported that the microbiome AUTISM - MICROBIOTA - ANIMAL profiles of ASD individuals, particularly those with comorbid gastrointestinal dysfunction, differ from MODELS control groups. More than half of the children Epidemiological studies have identified with autism have gastrointestinal problems. In exposure to infection in the neonatal period as a The role of intestinal flora in autism and nutritional approaches 63 risk factor for a number of neurological disorders offspring. These factors cross the placenta, affect such as autism and schizophrenia. Immunogen the development of the neuronal circuits of the activation (MIA) is performed with propionic acid offspring, impair the behavioral phenotype and (PPA), valproic acid (VPA), lipopolysaccharide increase the risk of developing ASD.[26] A study (LPS) or polycytidylic acid: (i.e. poly(I:C)) to create found that mothers whose pre-pregnancy weight a model of autism in mice. Autism-like behaviors, is over 90 kg are more likely to develop autistic including impaired communication, were observed children. Therefore, a clear relationship can be particularly in male rats by administering PPA established between obesity during pregnancy mg/kg for three days or giving LPS 100 μg/kg and ASD formation in offspring. Factors such intraperitoneally to create a rodent model with as the mother's age, diet, mode of delivery and autistic characteristics. In additional method, environment and stress have been evaluated autism symptoms occur when VPA is dissolved in as perinatal factors in autism by affecting the saline by intraperitoneal injection and administered microbiota-gut-brain axis.[27] 600 mg/kg on Day 12.5 of embryonic pregnancy. Genes related to social behavior were found to be AUTISM - GUT-BRAIN AXIS decreased in the hippocampus of these rats.[19-22] When the mice were examined behaviorally with The interaction between the intestinal flora the Dyadic social interaction test, they showed and the CNS works bidirectionally with a system increased repetitive behavior, diarrhea, decreased called the “Gut-Brain Axis”. This communication sociability and decreased mobility compared to network is formed by the CNS, brain and spinal the control groups. cord, autonomic nervous system, enteric nervous system, hypothalamic pituitary adrenal (HPA) When ASD human intestinal microbiota axis.[28] The HPA is a part of the limbic system donors were transplanted into germ-free mice, and is an important region of the brain in autism, autistic behaviors were induced. These behavioral mainly related to memory and emotional behavior. disorders caused by ASD microbiota were more The vagus nerve can sense microbiota metabolites [19] prominent in male mice. Studies have found that through sensory fibers and transmit them from the blood-brain barriers of mice known as germ- the intestine to the CNS. Short chain fatty acids free are permeable. Morphological differences produced by microorganisms in the microbiota were observed in these mice, particularly in the activate vagal sensory fibers. Propionate, in amygdala and hippocampus. Intestinal microbiota particular, from the accumulation of short-chain is involved in neuronal communication with fatty acids, has been shown to have broad effects molecules such as dopamine, glutamate, and on the CNS and cause developmental delays or serotonin, which are effective in key pathways such seizures.[29] Toll-like receptors are located on vagal as citrate cycle, synaptic long-acting potential, sensory fibers and these fibers can detect bacterial c-AMP mediated signaling and these systems products such as lipopolysaccharide and activate affect social skills in animals.[23] the brain. Microorganisms affect neurotransmitter production by vagus innervation. Microorganisms AUTISM - PERINATAL FACTORS may affect the levels of neurotransmitters According to academic studies, the diversity such as gamma-aminobutyric acid, serotonin, of microbiota that occurs in the perinatal period norepinephrine and dopamine.[30] It has been has a lifelong effect on natural killer cells.[24] The suggested that abnormal microbiota formed as maternal immune activation model that causes a result of these factors impairs the immune neuroinflammation in the brain developing in system by affecting lymphocyte migration and ASD pathogenesis causes long-term changes in differentiation in the gastrointestinal system. the microbiota and behavioral disorders in young Microorganisms can cause disruption of the animals.[20,25] During development, in addition to intestinal epithelium layer by stimulating the fatty acids and sugars, satiety hormones such as release of various cytokines and chemokines. insulin and leptin and low-grade inflammatory Allergies can be observed as a result of increased factors caused by obesity may play a role in the immune activation against these antigens that deterioration of the neuroendocrine system and enter the systemic circulation.[30,31] Environmental in the neuronal circuits that regulate behavior in stress and high pro-inflammatory cytokines 64 D J Tx Sci activate this system, which in turn stimulates that more research is needed to make general the secretion of adrenocorticotropic hormone recommendations about diets that can be a (ACTH) from the pituitary gland through the treatment method for ASD. stimulation of corticotropin releasing factor (CRF) from the hypothalamus and induces cortisol GLUTEN-FREE/CASEIN-FREE DIET release from the adrenal glands. Cortisol is an TREATMENT IN AUTISM important stress hormone that affects many human organs, including the brain. Therefore, When gluten and casein proteins are not fully cells such as both neural and hormonal lines digested in individuals with autism, it may lead of communication, immune cells (astrocytes, to behavioral disorders. It has been hypothesized neuroglia), epithelial cells, enteric neurons, that abnormal metabolism of these two proteins smooth muscle cells, Cajal's interstitial cells, may result in excess opioid activity in the CNS. and enterochromaffin cells can influence the Therefore, eliminating gluten means eliminating activities of intestinal cells.[32] Consequently, these wheat, oats, barley or rye - all flours, breads, communication systems between the intestinal breadcrumbs, pasta, pastries and others. The microbiota and the brain are important pathways casein-free diet means no dairy products such as for autism. The disrupted flora lead differentiation breast milk, yoghurt, cheese, butter, cream or ice [43-45] in the hippocampus region of the brain through cream are restricted. It has been observed the bidirectional system between the brain and that most individuals with autism are addicted to the intestine. Dysbiosis in the microbiota can foods containing gluten and casein. It was thought also activate immune cells by activating immune that caseinomorphine and glutenomorphine functions. More studies are needed to improve compounds that cross the blood-brain barrier these system activities between the gut and the without being digested cause morphine addiction. brain in autism. In a study, this diet was applied to 120 individuals with schizophrenia and 149 autism. A total of 87% of children with autism were found to have NUTRITIONAL APPROACHES IN high titer immunoglobuline G gliadin and 30% AUTISM high titer trans indolyl acrylic glycine antibodies Most children with ASD experience anxiety against gluten or casein.[45] [33] about nutrition. Children with ASD have more Results of gluten-free and casein-free nutrition [34,35] food allergies than other children. Selective were tested in children with autism (n=30) eating, food refusal, food obsession is common and positive effects on physiological activity, problem eating behaviors reported in children behavioral problems like autism symptoms and [36] with ASD. In addition to rejecting fruits and no significantly difference was.[46] Since data vegetables, starches, snacks and processed foods supporting or refuting gluten-free and casein-free are the most common choices in children with ASD. nutrition in ASD is still insufficient, further long- Increased consumption of snacks and foods high term randomized controlled studies are needed. in calories can lead to excessive weight gain.[37,38] Diet has been suggested as a therapeutic measure KETOGENIC DIET THERAPY IN for ASD symptoms. During the diagnosis of ASD, some dietary interventions have been tried as a AUTISM treatment.[39,40] A number of nutritional strategies Ketogenic diet is a high-fat, low-carbohydrate have been explored to treat behavioral disorders diet and is an effective treatment for epileptic and accompanying intestinal distress, including patients who fail to respond to anticonvulsant gluten/casein-free diets, ketogenic diets (KDs) medication. Recent studies have revealed that or probiotic supplementation. Certain diets (e.g. KD application has positive effects on reducing gluten/casein-free diet, ketogenic diets) have been ASD symptoms. A KD during the period of six observed to help alleviate symptoms associated months and a control diet for two weeks were with ASD.[40-42] For the right interventions, applied to 30 ASD children without epilepsy detailed diet and supplements should be evaluated between the ages of 4 to 10. By the end of the and personalized diet therapies should be study, 18 children were able to adapt to the KD. prepared by a trained dietician. It is concluded The Childhood Autism Rating Scale (CARS) was The role of intestinal flora in autism and nutritional approaches 65 applied at the end of the diet process and it was fragilis 1¥109 MIA enabled the offspring to reported that CARS scores increased significantly develop autistic behavior.[52] Maternal high-fat diet in 10 children with ASD.[47] BTBR T+tf/J (BTBR) (mHFD) caused changes in the gut microbiome mice treated with KD also ameliorated typical and social withdrawal in offspring. In particular, ASD deficiencies related to myelin formation administration of Lactobacillus reuteri, not and white matter development/connectivity by administering other strains of probiotics can affecting neurotransmitter signaling pathways, reverse social behavior abnormalities except including glutamate, serotonin, neuronal nitric for repetitive behavior and anxiety. This again acid synthase and dopamine.[48] In addition, suggests the specificity of effects among probiotic BTBR mice were characterized by a different gut strains.[53] microbiota profile than controls. However, KD A study on hamsters in which autism-like was thought to be associated with a higher risk of behavior was induced by the administration of inflammatory and defective mitochondria. There PPA or clindamycin examined the therapeutic are studies that it worsens side effects such as effect of a three-week oral treatment with a constipation and reflux.[49] After the KD in mice mixture of Bifidobacteria and Lactobacilli strains. with autism and epilepsy models, sociability was Clindamycin and PPA increased brain glutamate improved in female mice and repetitive behaviors excitotoxicity in hamsters, causing Mg2+ and were reduced, but behavioral improvements [50] GABA depletion. According to previous studies were more limited in males. In another study, on experimental animals, Mg2+ deficiency, which children were administered KD to improve the causes excessive Ca2+ and glutamate, is among autism behavior observed after 600 mg/kg of the causes of repetitive and impaired social VPA administered to pregnant mice. Valproic behavior. Significant changes in oxidative stress acid offspring fed with KD showed improvements markers, particularly glutathione and vitamin C, in social behavior compared to VPA offspring fed were observed in the brains of hamsters in the [51] with standard diet. Ketogenic diet is a dietary PPA and clindamycin group. treatment method that should be under the supervision of a pediatrician and a dietician as it is All probiotic and prebiotic therapies were a difficult diet to follow and parents have problems found to have curative effects, but lactobacillus in its implementation. Although there are studies had the strongest effect.[54] In a randomized, in which KD therapy has positive effects on double-blind, placebo-controlled study of autism, more comprehensive studies are needed. 62 children with autism aged 3 to 16 years had Lactobacillus plantarum (daily dose, 10 PREBIOTICS and 4.5¥10 CFU) administrated for three weeks. The children were divided into two groups: PROBIOTICS - AUTISM Group 1, a placebo during the first nutrition Probiotics are non-pathogenic microorganisms period (3 weeks) and probiotics during the living in the intestinal lumen, such as second (3 weeks) and vice versa for Group 2. Lactobacillus, Lactococcus, Bifidobacteria, The behavioral/emotional impact of both dietary and Saccharomycetes that produce lactic acid. regimens (probiotic and placebo) was assessed Probiotics possibly reduce gut inflammation by a standardized Developmental Behavior through a variety of mechanisms, such as Checklist (DBC-P), but no significant difference reducing gut barrier permeability, down- was reported between the two groups.[55] regulation of inflammatory cytokines, and other Additional study included 30 ASD patients with immunomodulatory effects. Probiotics show age of 5 to 9 years, who were given a fortified therapeutic effects on the disturbed intestinal formula containing Lactobacillus acidophilus, flora. Prebiotics reduced stress response in rodent Lactobacillus rhamnosus, and Bifidobacteria and human studies. Its use in gastrointestinal longum for three months and then evaluated diseases such as diarrhea, inflammatory bowel through the Autism Treatment Evaluation diseases and irritable bowel disease has been Checklist (ATEC). Overall ATEC scores decreased effective in reducing autism symptoms.[7] In a significantly after probiotic treatment, and a study conducted in a maternal immune activation significant reduction in the severity of autistic (MIA) model, orally administered Bacteroides symptoms was reported in the speech/language/ 66 D J Tx Sci communication categories of ATEC.[56] A two- record of its use in the following centuries. center, randomized, placebo-controlled probiotic It has been used orally and rectally in veterinary study was conducted in New Zealand in children medicine since the 17th century. Warm camel stool followed up from birth to 11 years. Probiotics was used by German soldiers to treat bacterial were administrated to mothers from 35 weeks of dysentery during World War II. In 1958, FMT gestation to six months. Children were treated for was first applied in modern medicine. Considering up to two years from birth. Thus, worse behavior the connection between the gut and the brain, was observed with probiotics based on behavioral modulating the gut microbiome with antibiotics, regulation and scores.[57] probiotics, prebiotics, and FMT may be a viable therapeutic option. In FMT, a large number of In the reviewed studies, there is some common microbes from a healthy donor used evidence that prebiotic and probiotic applications to transform a dysbiotic gut microbiome into a improve the behavior of children with ASD. healthy microbiome. Evidence-based criteria for Probiotics have been observed to be beneficial in standard application of FMT have not yet been treating various psychological conditions such as defined. The donors should not have a history depression and anxiety. The hypothesis behind of antibiotic use, intravenous drug use, high risk these studies is that probiotics act through the sexual intercourse, tattoo or piercing, contagious, gut-brain axis to affect neurotransmission and neoplastic, metabolic, allergic or autoimmune mood states.[53-58] The system that provides diseases in the last three months. Stool material communication between the gut and the brain is should be at least 150 grams and should be called the gut-brain axis. The task of this system obtained six hours before application.[59-61] It is the secretion of specific enzymes according was recommended to take a mild laxative such to the type of nutrient and the regulation as magnesie calcinee the night before FMT of peristalsis.[58] Probiotics can affect various was performed. One hour before FMT, two neuroactive metabolites such as gamma-amino anti-diarrheal tablets of loperamide should be butyric acid (GABA) and serotonin. Serotonin administrated to keep the transplanted stool in the has been observed to be influenced by the intestines for a minimum of four hours.[62] Stool intestinal bacteria. There is a hyperactivation of can be diluted with water, salt water or milk. Then a gene encoding serotonin reuptake transporters, the stool suspension is obtained with a household particularly in individuals with ASD. Studies have hand mixer. It is passed through a gauze or coffee linked neuropeptide oxytocin to social behavior filter to remove solid particles. The resulting and the pathogenesis of ASD.[53-58] This may suspension is taken into 60 mL syringes. Stool be the mechanism by which probiotics affect suspension can be sent to the upper gastrointestinal the behavior of ASD children. Research in this tract via an esophagogastroduodenoscopy, area is currently limited. According to studies on nasojejunal tube, or nasogastric tube, and to the probiotic and prebiotic supplements, information lower gastrointestinal tract with a colonoscopy is insufficient. Although probiotic and prebiotic or retention enema.[60,63] One of the important supplements used as alternative treatments have questions is which way a stool suspension is been observed to provide substantial benefit, administrated to the patient. The correct route further designed, randomized, placebo-controlled of administration for gastrointestinal diseases in clinical studies are needed to determine the neuropsychiatric disorders is unknown. There appropriate strains, dosage and treatment timing. are no clinical studies in which FMT is applied to autistic patients. However, studies have been EFFECT OF FMT ON AUTISM performed on stool samples. Clostridium species Fecal microbiota transplantation has a have been found to be more in the stools of autistic 1700-year history. This forgotten treatment children than healthy children. It was reported method has been put into use again in the last that the autistic symptoms of two children after 50 years. The first known application of fecal FMT and the symptoms of five autistic children material for treatment was made by a Chinese after the application of Bacteriodes produced doctor Ge Hong in the fourth century. It has been in culture decreased.[12] In a study conducted used orally under the name of “yellow soup” in on 18 autistic children, each from a different patients with severe diarrhea. There is no medical family, for ASD treatment; colonic irrigation was The role of intestinal flora in autism and nutritional approaches 67 performed with a two-week antibiotic treatment high beneficial effect and their applicability with followed by a prolonged FMT with daily and appropriate approaches. There are not enough lower maintenance doses for 7-8 weeks using studies in the literature for fecal transplantation the high starting dose. They found a significant as another treatment approach. However, the reduction in GI symptoms at the end of treatment, studies observed showed a healing effect. It is including significant improvements in symptoms currently not possible to say that any nutritional of constipation, diarrhea, indigestion, and therapy and FMT are effective, as the studies abdominal pain.[64] Although the roots of FMT at conducted do not provide full effect in the the past, there are limited studies in the literature. treatment of autism. We believe that individual Fecal transplantation appears to be a promising approaches are important in patients with autism method to remove dysbiosis in autism to reduce spectrum diagnosis, and more comprehensive the effect of leaky gut flora on neuronal activities. prospective studies are needed, since it is not It is certain that more detailed clinical studies are clear that the dose and treatment period focused needed for it to be a relevant treatment method. on improving the microbiota will be administered in the long term. DISCUSSION In this review article, the role of intestinal Declaration of conflicting interests flora in autism and alternative treatment The authors declared no conflicts of interest with approaches as studies in the literature on dietary respect to the authorship and/or publication of this article. treatments, prebiotic-probiotic supplements and Funding fecal transplantation were reviewed. 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